Submissions for variant NM_001370466.1(NOD2):c.2474A>G (p.Asn825Ser)

gnomAD frequency: 0.00076  dbSNP: rs104895467

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000280478	SCV000329195	uncertain significance	not provided	2016-03-14	criteria provided, single submitter	clinical testing	The N852S variant in the NOD2 gene has been reported in several publications as a rare risk allele associated with Crohn disease in the Ashkenazi Jewish population (Tukel et al., (2004); King et al. (2006); Rivas et al., (2011); Zhang W et al., 2013). The NHLBI ESP Exome Sequencing Project reports N852S was observed with a frequency of 0.11% in 10/8600 alleles from individuals of European background, indicating it may be a rare (benign) variant in this population. The N852S variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret N852S in NOD2 as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001781424	SCV000397287	likely benign	Inflammatory bowel disease 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000336827	SCV000397288	likely benign	Blau syndrome	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002513883	SCV000759541	association	Blau syndrome; Regional enteritis	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 852 of the NOD2 protein (p.Asn852Ser). This variant is present in population databases (rs104895467, gnomAD 1.6%), including at least one homozygous and/or hemizygous individual. In a large association analysis involving over 40,000 cases and controls (PMID: 21983784), individuals who carried this variant had a significantly increased risk of Crohn's disease (OR=2.47, 95% CI=1.55-3.93). ClinVar contains an entry for this variant (Variation ID: 97856). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NOD2 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects NOD2 function (PMID: 21983784). In summary, this is a common variant that is associated with an increased risk for developing disease. For these reasons, this variant has been classified as an Increased Risk Allele.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000280478	SCV002049728	likely benign	not provided	2023-08-22	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002260984	SCV002542702	likely benign	Autoinflammatory syndrome	2021-01-29	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000280478	SCV002563338	benign	not provided	2024-06-01	criteria provided, single submitter	clinical testing	NOD2: BP4, BS1, BS2
Unité médicale des maladies autoinflammatoires, CHRU Montpellier	RCV000336827	SCV000116244	not provided	Blau syndrome		no assertion provided	not provided
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000280478	SCV001930578	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000280478	SCV001974024	likely benign	not provided		no assertion criteria provided	clinical testing